Dopaminergic Regulation of Prefrontal Cortical Pyramidal Cells in Schizophrenia

The prefrontal cortex (PFC) has long been a focus of investigation in schizophrenia. Recent postmortem and in vivo imaging studies studies have revealed a loss of PFC gray matter, but surprisingly, there is no overall decrease in neuronal number. A loss of volume in the face of the same number of cells can be explained by a loss of neuropil, which includes axons and dendrites. A number of postmortem studies have reported dystrophic dendrites of PFC pyramical cells in schizophrenia. Coupled with data indicating a decrease in the dopaminergic innervation of the PFC, we reasoned that a loss of dopamine may cause the dendritic remodeling. We have found that experimental disruption of the dopamine inputs to the PFC causes a decrease in dendritic length and spine density.

Similarly, we found that D1 receptor knockout mice also show dystrophic dendrites. Remarkably, we have been able to reverse the loss of dendritic elements by treating animals with an atypical, but not a typical, antipsychotic drug. Studies are ongoing to determine the phenotype of affected cells, and to examine the relative contribution of trophic factors and glutamatergic inputs.